Androgen Receptor and Cancer

Background:

One of the subjects I investigated during the past weeks is the role of androgen in cancer. Androgen receptors (AR) blockage is a treatment strategy used in e.g. prostate cancer, in order to stop or reduce cancer progression. However, as you will see from the papers cited below, and these are just a few out of a large number of publications on this subject, the androgen receptor has a very important role in tumor progression and its blocking alone may lead to cancer cell death in many tumor types.

I actually believe that just like for every problem there are multiple ways to solve it, hormones is one of the angles that is relevant for all cancers capturing a solution to every type of cancer. The difficulty is that there are so many hormones in the human body, interconnected like a spider web. However, beyond this complexity, it has been shown that e.g. thyroid hormones, and more specifically T4 (inhibition) may hold the answer to many types of cancers. (Ref.).

The high relevance of hormones for the human body is undebatable since hormones may even define who we are, how we think and how we look. At cellular level, hormones have impact on mayble all intracellular mechanisms, controlling even the membrane proton pumps such as Na/H exchange (Ref.), pumps that are highly relevant in cancers (Ref.).

Back to androgen receptors, I like the idea of focusing on AR blockage because that can be done relatively easy with various FDA approved drugs that have a well known safety profile. Wouldn’t be great if with one single and safe pill taken every day we could eliminate cancer? As you will see in the references below, that actually happened in patients with e.g. adrenal tumor and breast tumor. I am sure that if I search I will find many more case reports but the references below are enough to demonstrate the concept.

Androgen receptor-blocking agents: potential role in pancreatic cancer. http://www.ncbi.nlm.nih.gov/pubmed/11043816/ Confirmatory evidence has now come from a double-blind, placebo-controlled trial in patients with pancreatic cancer in which flutamide, the pure androgen receptor blocker, doubled survival duration over control patients.

Androgens Up-regulate the Insulin-like Growth Factor-I Receptor in Prostate Cancer Cells http://www.ncbi.nlm.nih.gov/pubmed/15753383 Agents targeting these signaling pathways (ERK ) or the IGF-IR itself should therefore be considered as a complement of standard anti-androgen therapy to induce tumor regression and possibly reduce the chance or delay the time of tumor progression to androgen independence.

Complete Response of Metastatic Androgen Receptor–Positive Breast Cancer to Bicalutamide: Case Report and Review of the Literaturehttp://jco.ascopubs.org/content/34/4/e21.full Approximately 10% to 32% of TNBC have androgen receptor (AR) expression.

Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo http://mct.aacrjournals.org/content/14/3/769 Our study indicates that multiple subtypes of AR+ TNBC depend on AR for proliferation, migration, and invasion, and tumor growth in vivo and provides promising preclinical data on the efficacy of enzalutamide in TNBC with low AR expression.

Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.http://www.ncbi.nlm.nih.gov/pubmed/27120467 Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. As VDR agonist they used Calcitriol.

Disappearance of a virilizing adrenal tumor following therapy with cyproterone acetate.http://www.ncbi.nlm.nih.gov/pubmed/16322333 As the patient refused surgery, virilization was treated with the antiandrogen cyproterone acetate (CPA), but for only 4 months because clinical and hormone abnormalities reversed and the tumor was no longer visible. The patient remains symptom-free. This first report of a curative effect of CPA on a purely virilizing adrenal tumor opens new avenues in the management of such tumors.

Androgen receptor inducing bladder cancer progression by promoting an epithelial-mesenchymal transition.http://www.ncbi.nlm.nih.gov/pubmed/24329492 It is concluded that suppression of AR expression decreased the production of TGF-β, inhibiting EMT and bladder cancer cell growth in vitro and in vivo, implying that its use might be a potential therapeutic target for the treatment of bladder cancer.

Source and Dose:

One example of AR blocker is Cyproterone Acetate, a substance that is also used in contraceptive pills. Cyproterone Acetate is cheap and available in most countries via local or online pharmacies. Some online pharmacies are selling it even without prescription. The dose that is typically used for contraceptive pills is in the range of a few mg/day while that used to block androgen receptors is in the range of 10 to 200mg/day. Because Cyproterone Acetate can also lead to some toxicity on the liver, I would prefer to stay in the 50mg/day dose range but you would need to check with your doctor.

Note that besides, Cyproterone Acetate there are many other androgen receptor blocking drugs commercially available. (Ref.) Even Cimetidine (an anti histamine safe drug that is a must in my view for every cancer patient to reduce chance for metastasis) seems to have anti androgen activity (Ref.).

However, in some cases, androgen receptor blockers may not be enough (Ref.). In that case, to have an effective treatment strategy, we may need to also reduce androgen production. This is typically done with drugs such as Ketokonazole, Abiraterone Acetate, etc. that reduce hormone production by inhibiting relevant enzymes at cellular level but also with GnRH modulators (discussed in an earlier post on this website) that lead to inhibition of the circulating hormones (released from the brain) and that in turn trigger the androgen production in adrenals and reproductive glands. Indeed, GnRH modulators alone are used by some clinics to treat various tumor types (Ref.).

Mechanism:

Androgens such as testosterone are synthesized primarily by the Leydig cells in the testes, under the regulation of luteinizing hormone (LH) produced by the anterior pituitary gland. LH secretion is in turn regulated by gonadotropin-releasing hormone (GnRH). Once produced, testosterone mostly circulates in the blood bound to serum sex hormone-binding globulin (SHBG) and albumin (Ref.)

Androgen Receptor blockers are also used in the treatment of hirsutism and other androgen-dependent conditions and as a component of hormone replacement therapy for transgender women. The drugs act as selective antagonists of the androgen receptor (AR), preventing androgens like testosterone and dihydrotestosterone (DHT) from binding to and activating the AR and exerting their biological effects in the body.

However, besides testosterone and dihydrotestosterone pathways, androgen receptors are facilitating many other cellular processes in the human body, of which some are very relevant to cancer development:

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

Thank you for your msg Carl! I do my best to share whenever I can and I am happy to hear that you appreciate that.
There is so much I would like to write on so many subjects … just that the challenges at home next to my full time job, takes sometimes all my time.

Yes Meech, although the testosterone is not inhibited by cyproterone-like drugs its receptors will and that will come with the low testosterone related side effects. Ketokonazole-like drugs will also lead to that (in high doses) but it will lower other hormones as well as it acts on an enzyme earlier in the pathway of the hormone production. Other drugs such as cholesterol lowering drugs (e.g. statins) may produce same kind of effects although lower in amplitude.

Hi Daniel
Take a look at some of the research by people such as Dr Abraham Morgentaler from Harvard, or Dr John Lee, on the effect of low testosterone on prostate cancer. They argue that low T has an adverse effect – hence it is usually older men that get prostate cancer. Dr Morgentaler has recently given a talk on this, in Europe. It should be on his website or you tube. I would be interested to hear your thoughts on this.

Indeed, it seems that man with congenital deficiency of 5AR have low levels of DHT, a diminutive prostate, and complete lack of prostatic glandular epithelium and are notable for a lack of reported cases of adenocarcinoma of the prostate. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699636/

So my feeling is that an answer may be found in 5AR which may increase its expression at older age (reference needed). If that is the case, at older age DHT will increase and lead to an increased chance for prostate cancer. On this line, you could argue that it is not Testosterone but its metabolite that is the problem.

If what dr. Morgentaler is showing is true than Testosterone injections may help reduce the chance for prostate cancer. I would have a wild explanation for that in the following way: injected T, will lead to reduced production of T in the prostate cancer cells (which also have the capability to produce testosterone https://www.cancer.gov/types/prostate/prostate-hormone-therapy-fact-sheet) via a feedback loop leading to reduction of LH. In this way there will be lower or no T and therefore DHT produced in the prostate cancer cells leading to decrease or stop in the proliferation.